title: Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita(+/Ins2)-derived β-cells.
abstract: Insulin release from pancreatic β-cells plays a critical role in blood glucose homeostasis, and β-cell dysfunction leads to the development of diabetes mellitus. In cases of monogenic type 1 diabetes mellitus (T1DM) that involve mutations in the insulin gene, we hypothesized that misfolding of insulin could result in endoplasmic reticulum (ER) stress, oxidant production, and mitochondrial damage. To address this, we used the Akita(+/Ins2) T1DM model in which misfolding of the insulin 2 gene leads to ER stress-mediated β-cell death and thapsigargin to induce ER stress in two different β-cell lines and in intact mouse islets. Using transformed pancreatic β-cell lines generated from wild-type Ins2(+/+) (WT) and Akita(+/Ins2) mice, we evaluated cellular bioenergetics, oxidative stress, mitochondrial protein levels, and autophagic flux to determine whether changes in these processes contribute to β-cell dysfunction. In addition, we induced ER stress pharmacologically using thapsigargin in WT β-cells, INS-1 cells, and intact mouse islets to examine the effects of ER stress on mitochondrial function. Our data reveal that Akita(+/Ins2)-derived β-cells have increased mitochondrial dysfunction, oxidant production, mtDNA damage, and alterations in mitochondrial protein levels that are not corrected by autophagy. Together, these findings suggest that deterioration in mitochondrial function due to an oxidative environment and ER stress contributes to β-cell dysfunction and could contribute to T1DM in which mutations in insulin occur.
authors.affiliation: Department of Pathology and.
authors.forename: Tanecia
authors.initials: T
authors.lastname: Mitchell
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Johnson
authors.forename: Xiaosen
authors.initials: X
authors.lastname: Ouyang
authors.forename: Balu K
authors.initials: BK
authors.lastname: Chacko
authors.forename: Kasturi
authors.initials: K
authors.lastname: Mitra
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Lei
authors.forename: Ying
authors.initials: Y
authors.lastname: Gai
authors.forename: D Ray
authors.initials: DR
authors.lastname: Moore
authors.forename: Stephen
authors.initials: S
authors.lastname: Barnes
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
authors.forename: Sasanka
authors.initials: S
authors.lastname: Ramanadham
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000032:analysis
chemical_list: D004272:DNA, Mitochondrial; D007328:Insulin; D013482:Superoxide Dismutase
keywords: diabetes mellitus; endoplasmic reticulum stress; mitochondrial quality control; mitochondrial respiration; β-cell